Hydrogenation of 5-unsaturated steroidal 16-ylidenalkylcarboxylic acids



United States Patent signors to Abbott Laboratories, North Chicago,111., a

corporation of Illinois No Drawing. Filed May 13, 1963, Ser. No. 280,1203 Claims. (Cl. 250-3971) The present application is directed to apartial hydrogenation. More particularly, it deals with the selectivehydrogenation of the side-chain double bond in certain .S-unsaturatedsteroidal l'6-ylidenalkylcarboxylic acids.

In the preparation of steroidlactones such as are described in US.3,045,012, and for other S-unsaturated steroids with saturatedside-chains at 16, selective hydrogenation of the side-chain double bondis necessary. In order to obtain certain therapeutically valuablesteroids, retention of the unsaturation of C-5(-6) is desirable.Platinum catalysts are best suited for the reduction of the side-chaindouble bond. The usual reactionconditions lead to a concurrent reductionof the S-double bond (see Fieser and Fieser, Steroids, ReinholdPublishing Corporation, New York, 1959, pp. 27, 28.). Wehave now foundconditions which permitthe use of platinum catalysts for the reductionof the side-chain Without aiiecting the S-double bond in the steroidalring system and Without necessitating the cumbersome procedure ofprotecting that double bond at 5.

It is an object of the present invention to hydrogenate the double bondat C-16 of steroid-l6-ylidenalkylcarboxylic acids and their esters. Itis another object of hydrogcnate such side-chain double bonds ofsteriods which possess ring-unsaturation at 05. It isa further object ofthe present invention to hydrogenate certain A -steroid-,-1'6-ylidenalkylcarboxylic acids or their esters to the correspondingsteroid acids or esters saturated at C-16 but without affecting the ringunsaturation between C-5 and C-6. V

These and other objects are accomplished by suspending 1-5 parts of acompound of the formula V Tonwnnmoon I o ona'iowherein R is hydrogen orlower alkyl and wherein n is an integer from 0 to 2, in 100 parts byvolume of alcohol in the presence of 15% of catalytic platinum based onthe amount of steroid and about 5 parts of water, and subjecting saidmixture to gaseous hydrogen until hydrogen uptake ceases. The alcoholused as the main reaction medium is a low-boiling alkanol, preferablymethanol or ethanol.

The starting materials mentioned above are those described in US.3,045,012.

The present invention is better understood by reference to the followingexamples which are given as illustrations only and are not meant tolimit the invention.

EXAMPLE 1 3,8,17p-diacet0xy-5-androsten-16fl-ylacetic acid (a) To asuspension of 0.086 gram of platinum oxide in 100 cc. of methanol and 5cc. of water, is added 4.3 grams (0.01 mole) of3,8,17fl-diacetoXy-5-andr0sten-l6- ylidenacetic acid. The suspension ishydrogenated in a 3,1d2237 Patented June 29, 19%5 ([7) When in the aboveexample glacial acetic acid is used as the reaction medium, there is atendency to- Ward reduction of the double bond in the 5-position. Ahydrogenation reaction carried out in this manner but interrupted afterone hour at room temperature produces a yield of only 33% of theexpected theoretical amount of3,6,17fi-diacetoxy-S-androsten-lfi-ylacetic acid while the remainder ofthe starting material is converted to S-Saturated and other compounds.

(c) In another repetition of the above example, 0.03 mole of startingmaterial is hydrogenated in cc. of methanol and 10 cc. of glacial aceticacid in the presence of 0.26 gram of platinum oxide. A fair yield of3,6,17 3-diacetoxy-5-androsten-lfifl-ylacetic acid is obtained ifhydrogenation is interrupted when the theoretically required amount ofhydrogen necessary to saturate the sidechain double bond is absorbed.Without stopping hydrogenation at exactly the proper moment, the yieldof desired material decreases.

(at) In another experiment carried out with the same starting materialsbut using pure methanol as the solvent, hydrogen uptake proceedsbeyondthe required uptake for the saturation of the side-chain double bondalone. When hydrogenation is interrupted as soon as the theoreticalamount of hydrogen is absorbed, 3/3,17,8-diacetoxy-"5-androsten-1SB-ylacetic acid is obtained in a yield of 58%. This yielddecreases if hydrogenation is allowed to continue without interruption.

EXAMPLE 2 3- (35,1 7/3-diacetoxy-5-andr sten-16fi-yl) propionl'c acidEXAMPLE .3

In analogy to the process of Example 1(a), two parallel runs are carriedout: in one flask, 4-(3,9,17,6-diacetoxy-5- androstend6-ylidene)butyricacid, and in the other flask the methyl ester of said compound, arehydrogenated and worked up as described above. The isolated end productsfrom both runs are the expected IG-saturated, S-unsaturated compoundsobtained in good yields.

The main advantage of the process of the present invention is the rapidand selective hydrogenation which does not aflfect the ring double bond.The present method provides a simple and fast means of hydrogenatingonly the desired side-chain double bond without the necessity ofwatching closely (and calculating) the amount of hydrogen absorbed,While it would be expected that the catalyst used herein would alsopromote saturation of the double bond at C-5.

The requirements for successful operation'of the proc I ess of thepresent invention are the use of a low-boiling alkanol as the solvent,the presence of about 5% by volume of water in the reaction medium, andthe use of a concentration of no more than about 5% of starting materialin the liquid reaction medium. If the amount of water in the system isdecreased substantially below the 5% limit given above, hydrogenationtends to proceed beyond the saturation of the side-chain double bond.However, with the above amount of water in the system, the reactionbecomes self-controlled, i.e., hydrogenation stops when the desiredreaction is completed.

It has been found through extensive experimentation that operation atconcentrations of about 5% of starting material in the liquid reactionmedium is preferred. If concentrations substantially above this limitare used, hydrogenation proceeds considerably slower, since the startingmaterials and reduction products are only sparing ly soluble in alcoholand alcohol/ water.

The platinum oxide used in the above examples may be substituted withother platinum catalysts and such catalysts can be'in the form ofchunks, pellets, powder or any other suitable form, including thecarrier-supported form. Amounts of about 2% platinum based on the amountof steroid material have been.found to be satisfactory, although amountsof from 1% to 5% will also produce good results. The reaction of thepresent invention can be carried out atroorn temperature, asdemonstrated in the examples, but a temperature range of from to 30 C.will produce equally good results. Since no extensive pressures arenecessary for satisfactory results in this reaction, the so-calledlow-pressure equipment such as Parr shakers or stills can be used.Hydrogen pressures of from just beyond atmospheric pressure to 100p.s.i.g. produce excellent results, but of course higher pressures maybe used if desired.

Although the above only demonstrates the process of the presentinvention with the free acid and the methyl esters, it will be readilyapparent that other esters are equally well suited as the startingmaterials, e.g., the ethyl, propyl or butyl esters.

Others may practice the invention in any of the numerous ways which willbe suggested by the present disclosure to one skilled in the art. Allsuch practice of the invention is considered to be a part hereofprovided it falls within the scope of the appended claims.

. We claim:

1. The process of-hydrogenating a steroid of the formula O O lCHa grTCEHCHQ no 0 o R 2. .The process of claim 1 wherein said hydrogenpressure is below p.s.i.g.

3. The process of claim 1 wherein said hydrogenation is carried out at atemperature of from 0 to 30 C.

References Cited by the Examiner UNITED STATES PATENTS 3,039,528 6/62Arth et al. 260397.4 3,089,874 5/63 Kurath et al. 260-3971 3,117,9661/64 Petrow 260239.55

OTHER REFERENCES l Fajkos: Collection Czech. Chem. Comm. (1959), vol.24, page 2284 relied on.

LEWIS GOTTS, Primary Examiner.

1. THE PROCESS OF HYDROGENATING A STEROID OF THE FORMULA